Aspirin inhibits the SHH/GLI1 signaling pathway and sensitizes malignant glioma cells to temozolomide therapy.
Aspirin inhibits the SHH/GLI1 signaling pathway and sensitizes malignant glioma cells to temozolomide therapy.
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阿司匹林抑制 SHH/GLI1 信号通路并使恶性胶质瘤细胞对替莫唑胺治疗敏感
DOI：
10.18632/aging.101224
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发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Jiang C
中科院分区：
文献类型：
--
作者：
Ming J;Sun B;Li Z;Lin L;Meng X;Han B;Wang R;Wu P;Li J;Cai J;Jiang C
音刺猬（sonic hedgehog，SHH）/胶质瘤相关癌基因同源物1（glioma-associated oncogene homolog 1，GLI 1）通路的异常激活在恶性胶质瘤细胞的致瘤性和替莫唑胺（temozolomide，TMZ）耐药中起重要作用。本研究以SHH/GLI 1通路为靶点，探讨了阿司匹林的靶向分子途径，并探讨了阿司匹林联合TMZ治疗的可行性。Western blot和定量实时聚合酶链反应（qRT-PCR）显示SHH/GLI 1通路的活性被阿司匹林强烈抑制。阿司匹林通过抑制SHH/GLI 1通路和重编程上皮细胞向间质细胞转化（EMT）发挥抑制胶质瘤生长和促凋亡作用。免疫荧光检测表明阿司匹林可以阻止GLI 1的核转位，从而抑制其转录调控。GLI 1的稳定慢病毒过表达逆转了由GANT 61和TMZ引起的DNA双链断裂（DSB）。此外，阿司匹林与TMZ联合使用可增强化疗敏感性，阿司匹林在体外和体内部分阻断GLI 1诱导的化学保护作用。总的来说，阿司匹林具有针对神经胶质瘤细胞的SHH/GLI 1靶向治疗的治疗潜力。GLI 1的获得性激活保护胶质瘤细胞免受TMZ治疗。DNA双链断裂修复活性受损可能参与阿司匹林诱导化疗敏感性的途径。阿司匹林联合TMZ可能是治疗恶性胶质瘤的一个有希望的策略。
Aberrant activation of sonic hedgehog (SHH)/glioma-associated oncogene homolog 1 (GLI1) pathway plays an important role in the tumorigenicity of malignant glioma cells and resistance to temozolomide (TMZ). Here we investigated the aspirin's antineoplastic molecular route by targeting SHH/GLI1 pathway and examined the feasibility of aspirin combined with TMZ therapy. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) revealed that the activity of the SHH/GLI1 pathway was strongly inhibited by aspirin. Aspirin acted as the glioma growth-inhibitory and pro-apoptosis roles by inhibiting the SHH/GLI1 pathway and reprogramming the epithelial to mesenchymal transition (EMT). The immunofluorescence assay showed aspirin could prevent the nuclear translocation of GLI1 to inhibit its transcriptional regulation. The stable lentiviral overexpression of GLI1 reversed the DNA double strand breaks (DSBs) caused by the GANT61 and TMZ. Furthermore, aspirin combined with TMZ enhanced chemosensitivity and GLI1-induced chemoprotection was partly blocked by aspirin in vitro and in vivo. Collectively, aspirin has a therapeutic potential for SHH/GLI1 targeted therapy against glioma cells. Acquired activation of GLI1 protects glioma cells against TMZ therapy. Impairment of DNA DSBs repair activity might be involved in the route of aspirin-induced chemosensitivity. Combined aspirin with TMZ may be a promising strategy against malignant glioma.